Quaternary ammonium salts of morpholinoethyl 3, 4, 5-trimethoxybenzoate



United States Patent Ofifice 3,350,396 QUATERNARY AMMONIUM SALTS FMORPHOLINOETHYL 3,4,5 TRIMETH- OXYBENZOATE John D. McColl, Quebec,Quebec, Canada, and (lenssimos Frangatos, Princeton, N.J., assignors toFrank W. Horner Limited, Mount Royal, Quebec, Canada, a

Canadian company No Drawing. Filed June 9, 1964, Ser. No. 375,417 (Cl.260247.1)

1 Claim.

This application is a continuation-in-part of application S .N. 97,859,filed Mar. 23, 1961, now abandoned.

taining such novel salts, agents and as inhibitors of acetylcholinesynthesis.

The novel quaternized salts of aminoalkyl esters of3,4,5-trimethoxybenzoic acid of the present invention are those havingthe general formula:

wherein R and R are so hydrocarbon radicals having 24 carbon atoms andmay,

group consisting of uene sulfonate.

The quaternary salts of the present invention may suitably be preparedby reacting the basic esters of 3,4,5-

trimethoxybenzoic acid with ethyl p-toluene sulfonate,

' ethyl iodide or ethyl chloride. The reaction may be run in anysuitable solvent, for example,

chlorine, bromine, iodine and p-tolpreparation of seven typical membersof the novel group invention.

. EXAMPLE I Ethiodide of ldiethylaminoethyl 3,4,5-trimethoxybenz0ateEXAMPLE II Ethiodide of diethylaminopropyl 3,4,5 -trimeth0xybenzoate Asolution of g. of diethylaminopropyl 3,4,5-trimethoxybenzoate and 10 ml.of ethyl iodide in 150 ml. of dry benzene was refluxed for 2 hours onthe steam cone. After cooling, a solid precipitate was removed byfiltration and the solvent was evaporated from the filtrate. Thecombined residues were dissolved in 5 ml. of isoamyl alcohol, treatedwith charcoal and filtered. Upon addition of 15 ml. of ethyl acetateimmediate crystallization occurred. A second recrystallization yielded6.5 g. (42.6%) of the ethiodide of diethylaminopropyl 3,4,5-trimethoxybenzoate.

Melting point: 188 C.

Formula: C19H3QINO5.

Analysis-Calculated: C, 47.41; H, 6.70; N, 2.91. Found: C, 47.39; H,6.63; N, 2.85.

EXAMPLE III Etlziodide of pyrrolzldinoethyl 3,4,5-trimethoxybenzoate Asolution of 10 g. of oxybenzoate in 15 ml. of

isoamyl alcohol-ethyl acetate as described in Example I and 6.7 g. (45%)of the ethiodide of pyrrolidinoethyl 3,4,5-trimethoxybenz0ate wasobtained.

Melting point: 162 C.

Formula: C 'I-I INO Analysis.-Calculated: C, 44.46; H, 6.06; N, 3.01.Found: C, 46.53; H, 6.21; N, 3.01.

EXAMPLE IV Ethyl bromide salt of pyrrolidz'noethyl3,4,5-zrimethoxybenz0ate Formula: C H BrNO Analysis-Calculated: C,51.68; H, 6.75; N, 3.35. Found: C, 51.58; H, 6.91; N, 3.86.

EXAMPLE V Ethyl bromide salt of diethylaminoethyl3,4,5-trintethoxybenzoate A mixture of 62.2 g. (0.2 mole) ofdiethylaminoethyl hygroscopic and formed a monohydrate.

Melting point: 151 C. Formula: C gH B1N'O 'H 'O. Y Analysis-Calculated:C, 49.05; H, 7.41; N, 3.28. Found: C, 49.27; H, 7.37; N, 3.19.

EXAMPLE VI Ethyl ptoluene sulfonate of pyrroliainoethyl 3,4,5-trimethoxybenzaate Patented Oct. 31, 1967 layer was separated and thewater layer was extracted FWH 376: Diethylaminoethyl3,4,5-trimethoxybenzoate twice with 100 ml. portions of benzene. Thecombined FWH 411: Ethiodide of diethyl aminoethyl 3,4,5-trimebenzenelayers were dried over sodium sulfate and dethoxybenzoate colorized withcarbon. After removal of the benzene FWH 377: Diethylaminopropyl3,4,5-trimethoxyunder reduced pressure, the residue was warmed to 145benzoate C. to remove any unreacted pyrrolidinoethanol. Ethyl p- FWH397: Ethiodide of diethylaminopropyl 3,4,5-tritoluene sulfonate (100 g.,0.5 mole) was added and the methoxybenzoate mixture was stirred andheated at 1404450 for 3 The following Tables II and III give the resultsin full P After allowing the mixtul'e to cool of in blood pressure inthe intact anesthetized cat when used isoamyl alcohol was added. Thelight brown solution was at an intravenous dose of 2 mgjkgfl decolorizedwith carbon and 400 ml. of ethyl acetate was added. The quaternary saltprecipitated promptly and TABLE 11 197.5 g. (77.6%) wasobtained. B1 (1PMelting'point: 149 C. Compound 00 ressure Duration Formula. Cz5H37O8NS(FWH No.) Loan (Mouse, mgJkg.) 33%: (min) Analysis.--Calculated: C,58.92; H, 6.92; N, 2.77.

Found: c, 59.05; H, 6.91; N, 2 .77. gg g 0 2 EXAMPLE VII i0 15 2 Ethylp-toluene sulfonate of dzethylammoethyl 40 0 3,4,5-trimethoxybenzoate i8Starting with 0.5 mole of the reactants 3,4,5-trimethi oxybenzoylchloride, diethylaminoethanol and ethyl pg6 3 toluene sulfonate, andusing the same procedure as above, 10 3 a yield of 179 g. (69.7%) of thequaternary salt was 50 7 obtained.

TABLE III Comparison Between Description 368 and 369 and 370 and. 371and 872 and 376 and 377 and 400 410 412 399 409 411 391 Increase inBlood Pressure lowering. 3X 7X 1. 5X 2X 0X 5X 5X Increase in duration oiefiect 0x 7. 5x 3x 5x 4x 18. 5x 2. 5x

Melting point: 131 C. As shown in Tables H and III, the quaternizationof Formula: C H O S. the aminoalkyl esters of 3,4,5-trimethoxybenzoateacid to A'nalysis.--Calculated: C, 58.68; H, 7.29; N, 2.74. form thequaternary aminoalkyl esters of 3,4,S-trimethoxy- Found: C, 58.90; H,7.26; N, 2.50. 40 benzoate, acid of the present invention produces asignifi- TABLE I Analyses M.P. Compound 0.) Formula Calculated Found 0rr N o H N FWH 409-12 thiodide of pyrrolidino-propyl 3',4,5 tri- 200C10H30IN05- 47. 00 6.31 2. 92 47. 90. 6. 37 2. s2

methoxy-benzoate. FXQH 402-Ethiodide 0tpiperidino-ethyl3,4,5-trbmetl10xy1,64. CNHJBINOA 47.00 6.31 2.92 40. 86 0.36. 2.69

(H1208 9. FWH 410-1; thiodide otpiperidino-propyl 3,4,5 tri- 193'C2BHSIINO5, 4s. 68 e. 54 2. s4 1 48. 39 o. 2. 0s:

methoxy-benzoate. FWH 412-Ethoidide ot=morph0lino-ethyl'8,4;5-tri- 187ClaHflINOi 44.91 v 5.86 2.01 43.45 0:22 3.10

methoxy-benzoate.

The following compounds, whi ch are aminoalkyl esters cant effect on theproperties of the compounds. Thus, the of trimethoxybenzoic acid, andtheir quaternized corn blood pressure lowering ability of the compoundswhen pounds of the present invention, were studied for their they werequaternized increased, by a factor of 1.5, to 7 effect on bloodpressure. times, with the duration of theeifect lasting for 2.5. to 18.5

FWH 368: Piperidinoethyl 3,4,5-trimethoxybenzoate times as 10mg- In theanesthetized intact normotensive cat do and 1 th d .th ,4,5-trimetho I;Z323 E Iodide of plpen moe yl 3 xy rat, the quaternized compounds ofthe. present invention FWH 369: Piperidinopropyl3,4,,s4fimethoxybenzoate produce a pronounced fall in arterial bloodpressure atdoses from 0.25-2 mg./kg. The duration of the fall is de-,4,5-t gg sgg itg of plpendmopropyl 3 mm pendent upon the dose: theabsolute fall with increasing FWH 370: Morpholinoethyl'3,4,5-trimethoxybenz0ate (10156 is much less efiqcted than is theduration of this FWH 412: Ethiodide of morpholinoethyl3,4,5-trimetheffect- No tachyphyl'txls was bserved' Present oxybenzoatepounds are also active by oral administration although FWH 371:Pyrrolidinoethyl 3,4,5-trimethoxybenzoate 7 doses are naturallyrequlred- FWH 399; Ethiodide of pyrrolidinoethyl, 3,4,5-trimet spmal cator (animals which the spinal thoxybenzoate cord is separated from thebrain at the level'of the 1st or FWH 72; pyrroiidinopmpyl 3 4 s' t i thoyben o t 2nd cervical vertebrae) the depressor response of all theFWH-409; Ethi did f lidi l 3,4,54 iquaternized compounds of the presentinvention is methoxybenzoate 7 markedly reduced. A small fall inpressure is observed but the dose required to produce this fall is 1040times greater than that required in the intact animal.

The quaternized compounds of the present invention.

In tests conducted to date it appears that FWH 399 and FWH 411 have thelongest duration of action. While it is not desired to be limited to anyparticular theory, it appears that the compounds of the presentinvention are active in producing a depressor response of blood pressurelargely by a central mechanism. The peripheral parasympathetic blockingactivity appears to be of secondary importance and the potency of theactivity varies with the compound, but adds to the therapeuticusefulness of the invention.

The quaternized compounds of this invention are also elfective inreducing increased blood pressure in experimental animals. In the ratmade hypertensive (by the excision of one kidney, constriction of theremaining kidney and given prednisolone-chronic renal hypertensiveanimal), FWH 411, for example, is eflective in producing a fall inarterial blood pressure. Similarly in the acutely hypertensive dog(denervated carotid sinus), FWH 411 and FWH 399 produce a good fall inarterial blood pressure.

In addition, the compounds of the invention are useful as inhibitors ofacetylcholine synthesis. Direct evidence of this elfect was obtained byincubating minced mouse brain at 37 C. for one hour in eserinizedbicarbonate Lock solution, at a pH of 7, and in the presence of carbondioxide and oxygen. It was found that acetylcholine synthesis wassignificantly inhibited by the novel compounds of the invention. Forexample,

benzoate (FWH-429), at the above-stated concentration, producedsubstantial inhibition of the acetylcholine synthesis.

The compounds of the present invention may be formed preparation byadmixture with into a pharmaceutical a pharmaceutically acceptable,ingestible carrier.

An example of such a preparation is as follows:

Each tablet contains:

Active ingredient Starch Lactose Magnesium stearate (lubricant 7 m-ls.granulating solution 10% PVP in isopropyl alcohol for 100 tablets) bloodpressure in the human species.

We claim:

p-toluenesulfonate salt.

References Cited UNITED STATES PATENTS 2,844,621 6/1958 Bernstein 2604732,907,764 10/ 1959 Voegtli et a1. 260-268 3,013,054 12/1961 Richter260473 3,086,911 4/1963 Brown 16765 3,089,819 5/1963 Short l6765 ALEXMAZEL, Primary Examiner. J. S. LEVITI, HENRY R. JILES, Examiners. G. D.GOLDBERG, J. TOVAR, Assistant Examiners.

in the presence of the ethiodide of pyrrolidinoethyl3,4,5-trimethoxybenzoate (FWH-399),

The compounds of the present invention have been demonstrated to producea fall in systolic and diastolic blood

